Atherosclerotic coronary artery disease is a major cause of death all over the world. Acute atherosclerotic events are caused by changes in plaque composition that eventually lead to plaque rupture or erosion. Two major events that promote this so-called plaque vulnerability are macrophage inflammation and apoptosis. In cardiovascular diseases, high-density lipoprotein (HDL), a self-assembled nanoparticle (NP) of lipids and apolipoprotein-I (apoA-I) popularly termed as good cholesterol, is known to have a protective role. Therefore, development of targeted nanotechnologies for noninvasive imaging of apoptotic macrophages for vulnerable plaque detection and the initiation of preventative therapies that exploit the vascular protective effects of HDL could reduce the morbidity and mortality of coronary heart diseases. The Principal Investigator's laboratory recently developed a completely synthetic yet biodegradable HDL mimicking NP. With this success, we hypothesized that development of a new diagnosis and therapeutic options using a macrophage targeted NP that uses HDL and apoA-I components, collapse of mitochondrial membrane potential (??m) as an indicator of macrophage apoptosis, and contains nanoscale contrast agents iron oxide (IO) crystals for magnetic resonance imaging can provide an excellent alternative diagnosis-based treatment approach of atherosclerosis. This hypothesis was constructed based on the fact that macrophages are capable of taking up excess cholesterol, and it is well known that delivery of cholesterol to the mitochondria is the rate- limiting step fo cholesterol degradation in the liver. Therefore, a mitochondria targeted HDL mimicking NP will be able to carry excess cholesterol from cytosol to the mitochondria of macrophages to play an important role in the maintenance of intracellular lipid homeostasis. To construct this NP platform and to demonstrate its potential, we have defined the following Specific Aims: (1) Construction and in vitro optimization of a macrophage and ??m targeted HDL mimicking NP containing IO for plaque detection and preventive therapy; (2) Safety and toxicities of HDL mimicking NPs in mice and combined imaging and therapy in atherosclerotic mice; (3) Combined imaging and therapy in atherosclerotic Yucatan mini swine model. Although atherosclerotic cardiovascular disease accounts for more death and disability than all cancers combined, there are no national screening guidelines for asymptomatic atherosclerosis, and there is no government or healthcare sponsored reimbursement for atherosclerosis screening. If successful, this proposed research could be used to provide targeted therapies to all individuals with a positive test for atherosclerosis.